Hadjiolov N, Bitsch A, Neumann H G
Department of Toxicology, University of Würzburg, Germany.
Cancer Lett. 1995 Nov 27;98(1):39-46.
2-Acetylaminofluorene (2-AAF) is a complete carcinogen in rat liver. To investigate the specific properties, that distinguish 2-AAF from incomplete carcinogens, rats were fed 0.02% AAF in the diet for 6, 12, 16 weeks and some indicators of genotoxic and chronic toxic effects were studied immunohistochemically. GST-P, a marker for single initiated cells and preneoplastic foci, was induced in response to 2-AAF exposure. The effects were slight after 6 weeks of feeding, after 12 weeks GST-P-positive preneoplastic foci were present. The proto-oncogenes c-fos and c-jun are induced by several tumor promoters. In the present study c-FOS protein levels were increased in all 2-AAF treated animals at early stages not only in preneoplastic foci. However, all GST-P-positive foci were also c-FOS-positive. Surprisingly c-JUN was not enhanced in GST-P positive foci. It was comparatively expressed in hepatocytes and bile duct cells in all animals. We did not observe any immunolabeling for p53, either in preneoplastic foci or in hepatocytes from treated animals. A significant increase of apoptoses was noted in the whole liver lobule but also gathered in groups in the periportal area. The results support our proposal that oxidative stress and energy impairment in the mitochondria of periportal hepatocytes trigger morphological alterations in the rat liver.
2-乙酰氨基芴（2-AAF）是大鼠肝脏中的一种完全致癌物。为了研究区分2-AAF与不完全致癌物的特定特性，给大鼠喂食含0.02% AAF的饲料6周、12周、16周，并通过免疫组织化学方法研究了一些遗传毒性和慢性毒性效应指标。GST-P是单个起始细胞和癌前病灶的标志物，在接触2-AAF后被诱导。喂食6周后效应轻微，12周后出现GST-P阳性癌前病灶。原癌基因c-fos和c-jun可被多种肿瘤启动子诱导。在本研究中，早期所有接受2-AAF处理的动物中，不仅癌前病灶中c-FOS蛋白水平升高。然而，所有GST-P阳性病灶也都是c-FOS阳性。令人惊讶的是，GST-P阳性病灶中c-JUN并未增强。它在所有动物的肝细胞和胆管细胞中相对表达。在处理动物的癌前病灶或肝细胞中，我们均未观察到p53的任何免疫标记。在整个肝小叶中均观察到凋亡显著增加，且在门静脉周围区域成群聚集。这些结果支持了我们的观点，即门静脉周围肝细胞线粒体中的氧化应激和能量损伤引发了大鼠肝脏的形态学改变。
